PROJECT SUMMARY/ABSTRACT The Immunology Program includes 30 members (26 primary, 3 associate, 1 adjunct) from 9 departments. The program is led by Dr. James Allison, an international authority on exploring fundamental mechanisms of the immune response and checkpoint control, with co-leaders Dr. Jeffrey Molldrem, providing expertise in stem cell and translational research, and Dr. Patrick Hwu, lending his extensive experience in novel vaccines and adoptive T-cell therapies. The scientific goal of the Immunology Program is to conduct important studies in basic immunology and translate the findings into effective cancer immunotherapy. The program focuses on 4 themes: 1) immune regulation, 2) immune checkpoint blockade, 3) cancer vaccines, and 4) T-cell therapies, each with a specific aim: Aim 1: To understand fundamental mechanisms involved in regulating innate and adaptive immune responses. Aim 2: To elucidate fundamental cellular and molecular mechanisms of immune checkpoints and their impact on the tumor microenvironment by using preclinical models and clinical trials to identify the basis for failure of response to therapy or relapse. Aim 3: To identify novel targets for cancer vaccine development that will enable vaccination strategies to be more widely applied to the prevention and treatment of cancer. Aim 4: To improve the success rate of T-cell-based therapies using a combinatorial approach (T-cell therapy and checkpoint control) to improve clinical responses. Work on the Immunotherapy Platform, led by program members Drs. Allison, Padmanee Sharma, and Hwu and funded by the cancer center, spans multiple aims and serves as a mechanism to foster iterative cycles of translation between basic and clinical work by providing immune monitoring of patient samples and driving new preclinical and clinical studies by generating mechanistic data to inform rational design of new drug combinations. As of May 1, 2018, 3,434 patients have been enrolled across 118 different clinical trials. Annual direct peer-reviewed funding for the Immunology Program is $6.4M, with $1.9M (30%) from NCI grants and $4.5M (70%) from other peer-reviewed sources. Since the last submission, the program has produced 464 published papers: 184 (40%) are intraprogrammatic collaborations, 250 (54%) are interprogrammatic collaborations, and 278 (60%) are external collaborations. Sixty-five percent of articles appeared in journals with IF >5, and 31% appeared in journals with IF >10, including N Engl J Med, Nature, Cell, Science, Cancer Discov, Immunity, and Proc Natl Acad Sci USA. Program members use all 14 shared resources. Notable accomplishments during the last grant period included the demonstration that anti- CTLA-4 and anti-PD-1 therapies act on distinct T-cell populations, providing an explanation for the benefit achieved by combined therapy, and discovery of a positive correlation between gut microbiome diversity and response to immune checkpoint blockade therapy that is transferred along with fecal transplants. See the Program Highlights for other noteworthy accomplishments.